In this study, 157 patients with mCRPC and targeted exome sequencing of biopsies obtained after metastatic diagnosis were identified. Time from next-generation hormonal therapy (abiraterone/enzalutamide)or docetaxel start to clinical/radiographic progression (time to treatment failure) was estimated by Kaplan-Meier method, with censoring at next therapy or last follow-up for non-progressors.
Among the 103 evaluable patients, 80.1% had bone and/or lymph node-only metastases at mCRPC diagnosis. In total, 84.5% and 59.2% received next-generation hormonal therapy and docetaxel for mCRPC, respectively. Median overall survival was 4.5 years from first mCRPC. The frequency and predictive association of selected recurrently-altered genes are as follows:
PTEN alterations were associated with worse time to treatment failure on next-generation hormonal therapy, but not docetaxel; a similar trend was observed with BRCA2. Biallelic RB1 loss was strongly predictive, conferring significantly shorter time to treatment failure on both next-generation hormonal therapy (HR 1.76, 95% CI 0.96-3.21)and docetaxel (HR 2.30, 95% CI 1.10-4.81):
A score based on presence of tumor PTEN alterations and/or biallelic RB1 alterations was predictive of time to treatment failure on next-generation hormonal therapy (median time to treatment failure of score 0 vs 1 vs 2: 14.7 vs 12 vs 3.8 months; log-rank p=0.003).
Several conclusions can be drawn from this study:
- Compound tumor suppressor variants, driven by biallelic RB1loss present in 12% of tumors, are associated with shorter time to progression on both next-generation hormonal therapy and docetaxel therapy
- PTEN loss and TP53 loss compound RB1 loss in driving progression on therapy and shorter survival
- BRCA1/BRCA2 alterations were associated with poorer overall survival (OS) but no difference in time to progression on next-generation hormonal therapy or docetaxel
Co-Authors: Himisha Beltran, Atish Dipankar Choudhury, Christopher Sweeney; Dana-Farber Cancer Institute, Boston, MA; Weill Cornell Medical College, New York, NY; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA